Issue 14: The Importance of Planning for COVID-19 Vaccine Trials in Children

Jul 22, 2020

By Carol M. Kao / Evan J. Anderson / Walter A. Orenstein

Vaccinating children against SARS-CoV-2 has the potential to provide both direct and indirect benefits and requires consideration.  

There are over 150 COVID-19 vaccine candidates in various stages of development, including 24 that are already in clinical trials. Given the epidemiology of severe cases and deaths from COVID-19, vaccine development efforts have primarily focused on adults and high-risk populations, such as the elderly. There has been notably little discussion about conducting vaccine clinical trials in children. But children can develop life-threatening diseases and may contribute to adult infections, therefore planning for trials in children is an important component of the COVID-19 response.

SARS-CoV-2 Infection in Children

Although children represent a small proportion of total SARS-CoV-2 cases and hospitalizations in the US, a subset of children develop a severe inflammatory syndrome with Kawasaki disease-like features, now termed multi-system inflammatory syndrome in children (MIS-C), following infection. Children who are infected with SARS-CoV-2 are more likely to have mild symptoms or be asymptomatic. As a result, they are less likely to be seen by a healthcare provider or even be tested for the virus, and therefore, our current estimates may not reflect the true incidence in children. 

School and daycare closures in many communities were followed by decreases in COVID-19 cases in those communities, suggesting children may be playing an important role in transmission. Further studies regarding the role children may play in SARS-CoV-2 community transmission are urgently needed. Preliminary evidence suggests that children may have prolonged SARS-CoV-2 viral shedding based on detectable RNA in nasopharyngeal and stool samples, although whether this represents transmissible virus is unclear. Detection of SARS-CoV-2 in stool raises the possibility of fecal-oral transmission, which would pose a substantial risk to child caregivers and other critical adult members of society with frequent contact with children such as teachers, daycare workers, and healthcare providers.

Considerations for COVID-19 Vaccine Clinical Trials

Vaccinating children against SARS-CoV-2 also has the potential to provide both direct benefit and indirect benefit through community protection as observed with other respiratory pathogens. For example, dramatic declines in invasive pneumococcal disease (IPD) occurred after the introduction of heptavalent pneumococcal conjugate vaccine (PCV7) in children in 2000 and again after introduction of the PCV13 vaccine in 2010, but before adult PCV13 vaccination. Additionally, rubella and congenital rubella syndrome (CRS) were eliminated in the US following introduction of rubella-containing vaccines into the childhood immunization schedule to interrupt transmission to pregnant women. The role children played in transmitting each of these pathogens to adults was under-appreciated until after implementation of widespread pediatric vaccination. 

Regulatory approval for a COVID-19 vaccine in children will require pediatric data. Planning for COVID-19 vaccine clinical trials in children should begin as soon as safety data is available from Phase I and II trials in adults. To minimize safety concerns, older healthy children can be enrolled first, followed by younger cohorts. Whether a single-dose or multiple doses of vaccine are needed to generate a protective immune response will need to be determined and may vary based on age (children younger than nine who receive seasonal influenza vaccine for the first time require a booster dose). In Phase III trials, long-term safety will need to be demonstrated in large cohorts of children.

Presuming a correlate of protection is identified from adult vaccine clinical trials or natural history data, it may be necessary to make the primary endpoint immunogenicity (e.g., seroconversion defined by four-fold change in antibody titer from baseline) rather than vaccine efficacy to facilitate licensure by the US Food and Drug Administration, as it is unlikely that pediatric clinical trials will be powered to demonstrate protection against symptomatic COVID-19.

COVID-19 Vaccine Implementation in Children: Why it Makes Sense 

Widespread implementation of a COVID-19 vaccine program will be challenging, particularly soon after licensure. Given the limited supply of vaccine that will be immediately available, it may be prudent not to focus initial efforts on high-risk adults (the elderly and immunocompromised) because of their impaired immune responses to vaccines. Instead, focusing on vaccinating the persons who transmit the virus to these high-risk groups may work better, and as noted above, children may be important transmitters. 

Another potential advantage in vaccinating children is that pediatrician’s offices have existing infrastructure for distributing and handling large quantities of vaccines, and the US Vaccines for Children (VFC) program would ensure any licensed vaccine recommended by the Advisory Committee on Immunization Practices would be available to all children regardless of insurance or socioeconomic status. As detailed in a recent review, comprehensive systems are also already in place to assess vaccine safety post-licensure.

Our knowledge of the current SARS-CoV-2 pandemic is rapidly evolving. Recent infection trends across the US suggest a shift toward an increased number of younger adults and adolescents being infected after relaxation of social-distancing measures. With current estimates of disease prevalence well below the threshold needed for herd immunity, there is an urgent need for safe and effective COVID-19 vaccines. And given the direct and indirect benefits of vaccinating children, consideration should now be given to including children in COVID-19 vaccine trials.

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